title: Correlation between varying levels of PMP22 expression and the degree of demyelination and reduction in nerve conduction velocity in transgenic mice.
abstract: Charcot-Marie-Tooth disease type 1A is most commonly caused by a duplication of a 1.5 Mb region of chromosome 17 which includes the peripheral myelin protein 22 gene (PMP22). Over-expression of this gene leads to a hypomyelinating/demyelinating neuropathy and to severely reduced nerve conduction velocity. Previous mouse and rat models have had relatively high levels of expression of the mouse or human PMP22 gene leading to severe demyelination. Here we describe five lines of transgenic mice carrying increasing copies of the human PMP22 gene (one to seven) and expressing increasing levels of the transgene. From histological and electrophysiological observations there appears to be a threshold below which expression of PMP22 has virtually no effect; below a ratio of human/mouse mRNA expression of approximately 0.8, little effect is observed. Between a ratio of 0.8 and 1.5, histological and nerve conduction velocity abnormalities are observed, but there are no behavioural signs of neuropathy. An expression ratio >1.5 leads to a severe neuropathy. A second observation concerns the histology of the different lines; the level of expression does not affect the type of demyelination, but influences the severity of involvement.
authors.affiliation: Imperial College School of Medicine at St Mary's, London W2 1PG, UK. c.huxley@ic.ac.uk
authors.forename: C
authors.initials: C
authors.lastname: Huxley
authors.forename: E
authors.initials: E
authors.lastname: Passage
authors.forename: A M
authors.initials: AM
authors.lastname: Robertson
authors.forename: B
authors.initials: B
authors.lastname: Youl
authors.forename: S
authors.initials: S
authors.lastname: Huston
authors.forename: A
authors.initials: A
authors.lastname: Manson
authors.forename: D
authors.initials: D
authors.lastname: Sabéran-Djoniedi
authors.forename: D
authors.initials: D
authors.lastname: Figarella-Branger
authors.forename: J F
authors.initials: JF
authors.lastname: Pellissier
authors.forename: P K
authors.initials: PK
authors.lastname: Thomas
authors.forename: M
authors.initials: M
authors.lastname: Fontés
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D003711:Demyelinating Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004576:Electromyography; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007621:Karyotyping; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009185:Myelin Proteins / Q000096:biosynthesis* / Q000235:genetics*; D009431:Neural Conduction; D051381:Rats
chemical_list: D005819:Genetic Markers; D009185:Myelin Proteins; C073687:PMP22 protein, human; C489545:Pmp22 protein, mouse; C489546:Pmp22 protein, rat